Cytokines play pivotal roles in the development of autoimmune diseases. Cytokines are required for both activation and effector functions of inflammatory cells. The long-term goal of our research is to elucidate the mechanisms of cytokine action in autoimmune diseases. This proposal is based on our recent discovery that interleukin (IL)-6-deficient mice are completely resistant to experimental autoimmune encephalomyelitis (EAE), and are unable to develop a strong TH1 or TH2 type response to self- myelin antigens. The goal of this proposal is to elucidate the mechanisms of IL-6 action in animal models of multiple sclerosis. A major challenge to study the roles of cytokines in autoimmune diseases is that they are often produced by a variety of cell types that perform different functions. In the case of IL-6, it is produced not only by cells of the immune system that cause autoimmune inflammation, but also by cells of non-lymphoid tissues such as brain and spinal cord. While IL-6 may activate immune cells to induce autoimmune inflammation, it is also a potent neurotrophic factor that can prevent glia and neurons from inflammation-induced cell death. We hypothesize that IL-6 regulates autoimmune encephalomyelitis through two distinct pathways: 1) it promotes development of autoimmune inflammation by facilitating the activation, migration and effector functions of immune cells, and 2) it accelerates disease recovery by promoting growth and regeneration of neural cells, including oligodendrocytes. To test these hypotheses, we have developed four specific aims: I. The roles of IL-6 in the activation and differentiation of myelin-specific T cells in autoimmune encephalomyelitis. II. The roles of IL-6 in the formation of inflammatory lesions in autoimmune encephalomyelitis. III. The roles of IL-6 in apoptosis and disease recovery. IV. The roles of transcription factor NF-IL6 in autoimmune encephalomyelitis. These will be addressed by examining the consequences of IL-6 and NF-IL6 deficiency in various cell types using transgenic adoptive transfer and bone marrow chimeric models. Information generated from these studies may not only help elucidate the mechanisms of IL-6 action in EAE but also aid in developing novel strategies to treat autoimmune diseases such as multiple sclerosis.